Linkage ordinal data hm

Information about Linkage ordinal data hm

Published on August 7, 2007

Author: Haggrid

Source: authorstream.com

Content

Linkage Analysis with Ordinal Data: Sex-limitation:  Linkage Analysis with Ordinal Data: Sex-limitation Michael Neale, Marleen De Moor andamp; Sarah Medland Thanks to Fruhling Rijsdijk, Kate Morley et al whose slides we ripped off Boulder CO International Workshop March 8 2007 Overview:  Overview Background of ordinal trait modeling Introduction to sex-limitation theory Practical on sex-limited linkage analysis: Dutch twins’ exercise participation Ordinal data:  Ordinal data Measuring instrument is able to only discriminate between two or a few ordered categories e.g. absence or presence of a disease. Data take the form of counts, i.e. the number of individuals within each category: Of 100 individuals: 90 ‘no’ 10 ‘yes’ ‘no’ ‘no’ ‘yes’ ‘yes’ 8 19 18 55 Univariate Normal Distribution of Liability:  Univariate Normal Distribution of Liability Assumptions: (1) Underlying normal distribution of liability (2) The liability distribution has 1 or more thresholds (cut-offs) The standard Normal distribution:  The standard Normal distribution Liability is a latent variable, the scale is arbitrary, distribution is, therefore, assumed to be a Standard Normal Distribution (SND) or z-distribution: mean () = 0 and SD () = 1 z-values are the number of SD away from the mean area under curve translates directly to probabilities andgt; Normal Probability Density function () Two categorical traits: Data from siblings:  Two categorical traits: Data from siblings In an unselected sample of sib pairs andgt; Contingency Table with 4 observed cells: cell a:number of pairs concordant for unaffected cell d: number of pairs concordant for affected cell b/c: number of pairs discordant for the disorder 0 = unaffected 1 = affected Joint Liability Model for sib/twin pairs :  Joint Liability Model for sib/twin pairs Assumed to follow a bivariate normal distribution, where both traits have a mean of 0 and standard deviation of 1, but the correlation between them is unknown. The shape of a bivariate normal distribution is determined by the correlation between the traits Slide8:  Bivariate Normal r =.00 r =.90 Slide9:  Bivariate Normal (R=0.6) partitioned at threshold 1.4 (z-value) on both liabilities How are expected proportions calculated?:  How are expected proportions calculated? By numerical integration of the bivariate normal over two dimensions: the liabilities for twin1 and twin2 e.g. the probability that both twins are affected : Φ is the bivariate normal probability density function, L1 and L2 are the liabilities of twin1 and twin2, with means 0, and  is the correlation matrix of the two liabilities T1 is threshold (z-value) on L1, T2 is threshold (z-value) on L2 Slide11:  (0 1) (1 0) (0 0) (1 1) How is numerical integration performed?:  How is numerical integration performed? There are programmed mathematical subroutines that can do these calculations Mx uses one written by Alan Genz Slide13:  Liab 2 Liab 1 0 1 0 .87 .05 1 .05 .03 Expected Proportions of the BN, for R=0.6, Th1=1.4, Th2=1.4 Slide14:  How can we estimate correlations from CT? The correlation (shape) of the bivariate normal and the two thresholds determine the relative proportions of observations in the 4 cells of the contingency table. Conversely, the sample proportions in the 4 cells can be used to estimate the correlation and the thresholds. a d b c a c b d Summary:  Summary It is possible to estimate a tetrachoric correlation between categorical traits from simple counts because we assume that the underlying joint distribution is bivariate normal The relative sample proportions in the 4 cells are translated to proportions under the bivariate normal so that the most likely correlation and the thresholds are derived Next: use correlations in a linkage analysis Heterogeneity:  Heterogeneity Females Males What about DZO?:  What about DZO? Var F, Cov MZF, Cov DZF af, df, ef Var M, Cov MZM, Cov DZM am, dm, em Var Fdzo = Var F, Var M dzo = Var M Cov DZO rg (but still pihat) Homogeneity:  Homogeneity Heterogeneity:  Heterogeneity General Sex Limitation:  General Sex Limitation Practicalsex-limited linkagewith ordinal data in Mx:  Practical sex-limited linkage with ordinal data in Mx Slide22:  Data: Exercise participation Dutch sample of twins and their siblings N=9,408 individuals from 4,230 families Binary phenotype: Exercise participation: Yes/No (Criterion: 60 min/week at 4 METs) Slide23:  Genotyped sub sample Sub sample was genotyped N=1,432 sibling pairs from 619 families (MZ pairs excluded) (266 MM, 525 FF, 328 MF and 313 FM sib pairs) Genotypic information: based on 361 markers on average (10.6 cM spacing) IBD probabilities estimated at 1 cM grid in Merlin (multipoint) Pihat calculated in Mx with formula: Pihat=0.5*p(IBD=1)+1*p(IBD=2) Slide24:  Heritability in total sample Heritability estimates: Males: A 69.4% E 30.6% Females: A 55.7% E 44.3% Genetic correlation OS pairs: 0.27 Thus: partly different genes affect exercise participation in males and females Slide25:  Path model EXM EXF Ar,M EM Q Q Ar,F EF qM qF aM eM aF eF rAr,OS LIABEX, M LIABEX, F Slide26:  Mx script G2: Data from genotyped male-male sibling pairs Data NInput=346 Ord File=c19mm.dat … … Thresholds M +(S|R)*B ; Covariances A+E+Q | [email protected][email protected] _ [email protected][email protected] | A+E+Q ; … Slide27:  Mx script G1: Calculation group Data Calc NGroups=7 Begin Matrices ; X Lower 1 1 Free ! female genetic structure Z Lower 1 1 Free ! female specific environmental structure G Full 1 1 Free ! female qtl U Lower 1 1 Free ! male genetic structure W Lower 1 1 Free ! male specific environmental structure F Full 1 1 Free ! male qtl … Begin Algebra; A = U*U'; ! male genetic variance E = W*W'; ! male specific environmental variance Q = F*F'; ! male qtl variance V = A+E+Q; ! male total variance P = K*I; ! calculates pihat End Algebra ; … Slide28:  Mx script G6: constraint males: total variance=1 Constraint Begin matrices = Group 1; J unit nvar 1 End matrices; Constraint V=J; option no-output END … Slide29:  Exercise Run the script AEQc19.mx for position 11 on chromosome 19 Modify the script to test: for sex heterogeneity at QTL significance of QTL males significance of QTL females Obtain chi2 in the output and compute LOD scores for females and males with formula: LOD=chi2/4.61 If you have time, repeat this for another position on chromosome 19 Slide30:  Solution Modify the script: G5 … Option Multiple Issat END … Save full.mxs Get full.mxs !Test for sex heterogeneity Equate F 1 1 1 G 1 1 1 END Get full.mxs !Test for significance female QTL Drop G 1 1 1 END Get full.mxs !Test for significance male QTL Drop F 1 1 1 END Slide31:  Solution Results from Mx output: Slide32:  Results whole genome Males: Females: Slide33:  Issues Power to detect linkage (or heritability) with ordinal data is lower than with continuous data Power to detect sex heterogeneity at QTL also low Unclear what is best way to test sex-specific QTLs QTL variance is overestimated, leads to strange estimates in different parts of the model (aF, aM, rA,OS) Sex-limitation only considered here, but model applies to GxE generally. Slide34:  Sarah Medland (2005) TRHG More advanced scripting Efficient script to model sex-limited linkage, only 1 datagroup Both continuous and ordinal data Especially convenient when sibships are larger than 2 Slide35:  THE 20th ANNIVERSARY INTERNATIONAL WORKSHOP ON METHODOLOGY OF TWIN AND FAMILY STUDIES:  THE 20th ANNIVERSARY INTERNATIONAL WORKSHOP ON METHODOLOGY OF TWIN AND FAMILY STUDIES October 1 - 5, 2007 Leuven, Belgium

Related presentations


Other presentations created by Haggrid

makyaj
18. 06. 2007
0 views

makyaj

2407224601
22. 04. 2008
0 views

2407224601

0616PVR76491
17. 04. 2008
0 views

0616PVR76491

DART Slideshow
17. 04. 2008
0 views

DART Slideshow

AdvFin 2008 01 Introduction
10. 04. 2008
0 views

AdvFin 2008 01 Introduction

dept revenue presentation
09. 04. 2008
0 views

dept revenue presentation

het607 m06a01
07. 04. 2008
0 views

het607 m06a01

20061116 intl ops
30. 03. 2008
0 views

20061116 intl ops

2004 AMCHAM Doorknock
27. 03. 2008
0 views

2004 AMCHAM Doorknock

pdhpe moderate
18. 06. 2007
0 views

pdhpe moderate

Where the Red Fern Grows
03. 10. 2007
0 views

Where the Red Fern Grows

tutorial 1
19. 09. 2007
0 views

tutorial 1

Future Law Enforcement ppt
19. 09. 2007
0 views

Future Law Enforcement ppt

231B 2006 Suetterlin Lec1
12. 10. 2007
0 views

231B 2006 Suetterlin Lec1

Crocodile
12. 10. 2007
0 views

Crocodile

VLSI Symp 2 10 2007
09. 10. 2007
0 views

VLSI Symp 2 10 2007

2003 08 27 Schelle Wolff Carola
24. 10. 2007
0 views

2003 08 27 Schelle Wolff Carola

875 PERL 06 mini
02. 11. 2007
0 views

875 PERL 06 mini

Where the Sidewalk Ends
26. 10. 2007
0 views

Where the Sidewalk Ends

CNV
22. 10. 2007
0 views

CNV

pfit
07. 11. 2007
0 views

pfit

scholz
16. 11. 2007
0 views

scholz

DDR Frog Licking
17. 11. 2007
0 views

DDR Frog Licking

The Suffering of Jesus
17. 08. 2007
0 views

The Suffering of Jesus

lecture5
28. 11. 2007
0 views

lecture5

ontology
11. 12. 2007
0 views

ontology

predationmurray
01. 01. 2008
0 views

predationmurray

academy mission vision
03. 01. 2008
0 views

academy mission vision

Maldives presentation
07. 08. 2007
0 views

Maldives presentation

mood disorders
07. 08. 2007
0 views

mood disorders

Loh Verma Michalowski CPS04
07. 08. 2007
0 views

Loh Verma Michalowski CPS04

Karen Middleton
07. 08. 2007
0 views

Karen Middleton

modern Day Slavery
07. 08. 2007
0 views

modern Day Slavery

MOA Presentation Mandsager final
07. 08. 2007
0 views

MOA Presentation Mandsager final

oct15 insurance reinsurance RGA
07. 08. 2007
0 views

oct15 insurance reinsurance RGA

maldives khaleel
07. 08. 2007
0 views

maldives khaleel

peters HTC BlueGene CondorWeek
19. 09. 2007
0 views

peters HTC BlueGene CondorWeek

mostly oopsla03
19. 09. 2007
0 views

mostly oopsla03

2005 Loftus Introduced Fish
19. 11. 2007
0 views

2005 Loftus Introduced Fish

UNTITLED
07. 08. 2007
0 views

UNTITLED

knoblock
23. 10. 2007
0 views

knoblock

India US Dual Use Goldman
17. 08. 2007
0 views

India US Dual Use Goldman

RedSquare Bike Ride Eng
27. 09. 2007
0 views

RedSquare Bike Ride Eng

Financing EFA Maldives
07. 08. 2007
0 views

Financing EFA Maldives

Languages Models Factories
14. 11. 2007
0 views

Languages Models Factories

Ge11cDIfferentiation
20. 02. 2008
0 views

Ge11cDIfferentiation

1950s
24. 02. 2008
0 views

1950s

Dual Language Posterboard 2
24. 02. 2008
0 views

Dual Language Posterboard 2

200792013611855
10. 10. 2007
0 views

200792013611855

as2007 aviation careers brief
28. 02. 2008
0 views

as2007 aviation careers brief

BiodieselFuelQuality pt1
29. 02. 2008
0 views

BiodieselFuelQuality pt1

2005 Inflammation
04. 03. 2008
0 views

2005 Inflammation

MI 2006 final 11 9
07. 08. 2007
0 views

MI 2006 final 11 9

figuerola lucifer
15. 10. 2007
0 views

figuerola lucifer

TOXICVB
05. 01. 2008
0 views

TOXICVB

GENIe ISA
10. 03. 2008
0 views

GENIe ISA

Pretty Blue Planet
19. 09. 2007
0 views

Pretty Blue Planet

AM1 DTV China EN
11. 10. 2007
0 views

AM1 DTV China EN

2007RoyalEurope consumer
01. 11. 2007
0 views

2007RoyalEurope consumer

YTBv4
12. 03. 2008
0 views

YTBv4

SevenBrochure
26. 03. 2008
0 views

SevenBrochure

babar
15. 10. 2007
0 views

babar

memphis
23. 10. 2007
0 views

memphis

NASBE Asthma Policies
07. 08. 2007
0 views

NASBE Asthma Policies

Apache Harmony Short Talk
19. 09. 2007
0 views

Apache Harmony Short Talk

DSF
07. 01. 2008
0 views

DSF

Module 10 C Older Adults
07. 08. 2007
0 views

Module 10 C Older Adults

CEC 999 2006 018
11. 10. 2007
0 views

CEC 999 2006 018

NNER MAGAZIN neu
18. 06. 2007
0 views

NNER MAGAZIN neu

kids slide show
18. 06. 2007
0 views

kids slide show

Inco Present1
18. 06. 2007
0 views

Inco Present1

nifty fifty thrifty 2
18. 06. 2007
0 views

nifty fifty thrifty 2

Navigator
18. 06. 2007
0 views

Navigator

mudancas internas2 lila
18. 06. 2007
0 views

mudancas internas2 lila

MMC Selection271006
18. 06. 2007
0 views

MMC Selection271006

MD Rhythm Software
18. 06. 2007
0 views

MD Rhythm Software

Experian
19. 09. 2007
0 views

Experian

urb1
27. 11. 2007
0 views

urb1

presentation reunion cnds clubs
18. 06. 2007
0 views

presentation reunion cnds clubs

PMA Veri Sign Hot Trends
18. 06. 2007
0 views

PMA Veri Sign Hot Trends

Phys Act2 Ron Johnston
18. 06. 2007
0 views

Phys Act2 Ron Johnston

cdp 8 12 06
19. 09. 2007
0 views

cdp 8 12 06

cdp 12 06
19. 09. 2007
0 views

cdp 12 06

061101 Panofsky
17. 08. 2007
0 views

061101 Panofsky

Saints or Sinners
17. 08. 2007
0 views

Saints or Sinners

memoria
18. 06. 2007
0 views

memoria

00021386
19. 09. 2007
0 views

00021386

peso fall protection w
04. 01. 2008
0 views

peso fall protection w

irony
15. 06. 2007
0 views

irony

HOUSE HOLDER
15. 06. 2007
0 views

HOUSE HOLDER

god you are looking for
15. 06. 2007
0 views

god you are looking for

generadio7
15. 06. 2007
0 views

generadio7

friendship cinquain
15. 06. 2007
0 views

friendship cinquain

foreign words in english
15. 06. 2007
0 views

foreign words in english

FME UC 2006 Opening Session
15. 06. 2007
0 views

FME UC 2006 Opening Session

First fun in the afternoon
15. 06. 2007
0 views

First fun in the afternoon

feml fool 2006
15. 06. 2007
0 views

feml fool 2006

FATE AND CHANCE WEEK I 2006
15. 06. 2007
0 views

FATE AND CHANCE WEEK I 2006

FATE AND CHANCE WEEK 2 2006
15. 06. 2007
0 views

FATE AND CHANCE WEEK 2 2006

faq remarriage
15. 06. 2007
0 views

faq remarriage

faq commitment
15. 06. 2007
0 views

faq commitment

Fabulously Funny Facts
15. 06. 2007
0 views

Fabulously Funny Facts

NEW MEMBERS
18. 06. 2007
0 views

NEW MEMBERS

FOL and Prolog
15. 06. 2007
0 views

FOL and Prolog

mouton
18. 06. 2007
0 views

mouton

NPR
18. 06. 2007
0 views

NPR

NOWARonIran
16. 10. 2007
0 views

NOWARonIran

maendsregler
18. 06. 2007
0 views

maendsregler

Les arts figuratives al s XIX
01. 10. 2007
0 views

Les arts figuratives al s XIX

Kirkpatrick
07. 08. 2007
0 views

Kirkpatrick

texas emission
26. 02. 2008
0 views

texas emission

NFI Pact presentation copy 2
07. 08. 2007
0 views

NFI Pact presentation copy 2

casestudy
22. 10. 2007
0 views

casestudy

Thankyou Lord
17. 08. 2007
0 views

Thankyou Lord

megagreen
18. 06. 2007
0 views

megagreen

SRaha
17. 08. 2007
0 views

SRaha

Glasgow Anand
15. 11. 2007
0 views

Glasgow Anand

2 day training slideshow
07. 08. 2007
0 views

2 day training slideshow

Finch
15. 11. 2007
0 views

Finch